Genetic variation in the tumor necrosis factor-alpha promoter region and in the stress protein hsp70-2 - Susceptibility and prognostic implications in breast carcinoma

BACKGROUND. Tumor necrosis factor-alpha (TNF-alpha) and stress proteins (he at shock proteins) are determining factors in the immune response to tumor cells. The authors designated a large study to investigate the susceptibili ty and prognostic implications of the genetic variation in TNF-alpha and hs p70-2 in breast carcinoma. METHODS. The authors used the polymerase chain reaction and restriction enz yme digestion to characterize the variation of the TNF-alpha promoter regio n and that of the hsp70-2 gene in 243 unrelated Tunisian patients with brea st carcinoma and 174 healthy control subjects. Associations of the clinicop athologic parameters and the genetic markers with the rates of the breast c arcinoma specific overall survival and the disease free survival (DFS) were assessed using univariate and multivariate analyses. RESULTS. A highly significant association was found between TNF2 homozygous genotype and breast carcinoma (relative risk [RR], 4.44; P = 0.006). A hig h relative risk of breast carcinoma was found to be associated with one hsp 70-2 homozygous genotype (P2/P2; RR, 7.12; P = 0.0001). The TNF2 homozygous genotype showed a significant association with reduced DFS and/or overall survival by univariate test. Conversely P2-hsp70-2 homozygous genotype asso ciated with increased overall survival but not with DFS. Multivariate analy sis retained significance for TNF2 homozygous genotype as an independent pr ognostic indicator for both DFS (RR, 2.75; P = 0.01) and overall survival ( RR, 4.08; P = 0.01). CONCLUSIONS. Genetic variation in TNF-alpha and hsp70-2 may represent not o nly markers for the increased risk of breast carcinoma but also may predict the clinical outcome. (C) 2001 American Cancer Society.